One form of gene expression impairment by RNA-RNA duplex formation has been termed "antisense" inhibition. Exploitation of antisense gene regulation could lead to potent anti-viral therapy. A serious limitation of the antisense approach, especially as it applies to anti-viral activity, is that it is stoichiometric and may require large molar excesses of anti-sense versus target RNA to be effective.
Within recent years, discoveries of ribozymes, e.g., RNAs with enzymatic activities have led to the development of antisense molecules which not only form RNA-RNA hybrids, but catalytically cleave the covalent phosphodiester linkages and turn over large numbers of substrate molecules. Ribozymes can now be targeted to virtually any RNA transcript, and efficient cleavage can be readily achieved in vitro. See, Kim, S. H., et al. Proc. Natl Acad. Sci. U.S.A. 84:8788-8792 (1987); Haseloff, J., et al., Nature 234:585-591 (1988); PCT published application WO/89/05852; Cech, T.R. JAMA 260:3030-3034 (1988); PCT published application WO/88/04300; Jeffries, A. G., et al., Nucleic Acids Research 17:1371-1377 (1989).
U.S. Pat. No. 5,144,019 and application Ser. No. 401,613 describe stable, catalytically efficient ribozymes useful, inter alia, to cleave HIV-1 RNA or any other viral or endogenous cellular RNA in vitro and in vivo, mammalian cells transformed with such ribozymes, vectors useful to accomplish such transformation and the use for human therapy of such ribozymes whether produced synthetically or as expressed by such transformed cells. See Chang, et al. Clinical Biotechnology 2:23-31 (1990) which is incorporated herein by reference.